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Compounds having selective inhibiting effect at GSK3

a selective inhibitor and compound technology, applied in the field of compounds, can solve the problems of lithium intoxication, the back of axons and neuritis, and the inability to inhibit gsk3, and achieve good bioavailability

Inactive Publication Date: 2009-09-08
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides compounds with good bioavailability that selectively inhibit GSK3 and have a good selectivity profile. The compounds can be used for the treatment of various diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. The compounds have a simple structure and can be easily synthesized."

Problems solved by technology

This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy.
The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication.

Method used

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  • Compounds having selective inhibiting effect at GSK3
  • Compounds having selective inhibiting effect at GSK3
  • Compounds having selective inhibiting effect at GSK3

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide

[0049]To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6-bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride / ethanol, (9:1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H), 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m / z 294 (M++1).

example 2

N-[3-(4-Bromophenyl)propyl]-N,N-dicyclobutylamine

[0050]3-(4-Bromophenyl)propan-1-amine (0.50 g, 2.34 mmol; described in: Davies, R. V. et al. J. Chem. Soc. Perkin Trans. 1 1977, 2357-2364), cyclobutanone (0.393 g, 5.61 mmol) and acetic acid (0.140 mL, 2.34 mmol) were mixed in dichloroethane (6 mL) and stirred for 30 min. Sodium triacetoxy borohydride was added and the reaction mixture was stirred for 15 h. The reaction was quenched with water (15 mL) and extracted with methylene chloride (50 mL). The organic phase was separated, dried and evaporated. Purification by column chromatography using methylene chloride to methylene chloride / methanol, (2:1), gradient as the eluent gave 0.32 g (42% yield) of the title compound as colorless oil: MS (ESI) m / z 322 and 324 (M++1).

example 3

3-Amino-6-{4-[3-(dicyclobutylamino)propyl]phenyl}-N-pyridin-3-ylpyrazine-2-carboxamide Hydrochloride

[0051]n-Butyllithium (0.97 mL, 1.55 mmol) was added dropwise over 20 min to a cooled (−78° C.) solution of N-[3-(4-bromophenyl)propyl]-N,N-dicyclobutylamine (0.10 g, 0.31 mmol) and triisopropyl borate (0.21 mL, 0.93 mmol) in anhydrous tetrahydrofuran (2 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at −78° C. HCl (aq 3 M, 0.6 mL) was added to the reaction mixture and the mixture was allowed to warm to room temperature. Tetrahydrofuran (2 mL) was added, followed by sodium carbonate (1.1 g, 10.8 mmol), Pd(dppf)Cl2 (0.010 g, 12.2 μmol) and 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (0.10 g, 0.34 mmol). The mixture was heated to 65° C. for 15 h. The solvent was removed and purification by column chromatography on silica using a gradient methylene chloride to methylene chloride / methanol, (2:1), as the eluent gave a yellow solid. The solid was dissolved...

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Abstract

The present invention relates to new compounds of formula (I) wherein: Z is N and X is CH or N; Y is CONR5; P is phenyl or a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S; Q is phenyl or a 5 or 6 membered aromatic heterocyclic ring containing one or more nitrogen atoms; R is C1-6alkylNR10R11 or C1-6alkylazetidine; R10 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-61alkylheteroaryl or C1-6alkylNR8R9; R11 is C1-6alkylNR8R9, C0-6alkylC3-6cycloalkyl or C0-6alkylheterocycloalkyl; as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

FIELD OF THE INVENTION[0001]The present invention relates to new compounds of formula I, as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates to a process for the preparation of compounds of formula I and to new intermediates used therein.BACKGROUND OF THE INVENTION[0002]Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it.Alzheime...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A01N43/00A61K31/00A61K31/4965C07D241/02C07D401/00C07D403/00C07D405/00C07D409/00C07D411/00C07D413/00C07D417/00C07D419/00A61P3/10A61P5/48A61P15/18A61P17/14A61P25/00C07D401/12
CPCC07D401/12A61P15/16A61P15/18A61P17/02A61P17/14A61P21/04A61P25/00A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P31/18A61P37/04A61P43/00A61P5/48A61P9/00A61P3/10C07D401/14A61K31/49
Inventor BERG, STEFANHELLBERG, SVENSODERMAN, PETER
Owner ASTRAZENECA AB
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